Benzophenones such as 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (U.S. Pat. Nos. 5,236,952, 5,389,653, 5,476,875 and 5,563,371) are known catechol-O-methyl-transferase (COMT) inhibitors and are especially suitable for the therapy of Parkinson's disease and for the treatment of depressions and similar disease states.
Synthesis of 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (see U.S. Pat. No. 5,236,952, 5,389,653, 5,476,875 and 5,563,371 and Borgulya et al., Drugs of the Future (1991) 16, 719-721) is exemplary of benzophenone type COMT inhibitor synthesis.
The synthesis is based essentially on the reaction of 4-bromotoluene with 4-(benzyloxy)-3-methoxybenzaldehyde in the presence of butyllithium to give 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol. By oxidation to 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone and subsequent debenzylation there is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone. After regioselective nitration to 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone and subsequent hydrolysis of the methoxy group there is obtained the aforementioned inhibitor 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.
The above mentioned synthesis of other analogous catechol-O-methyltransferase inhibitors is described by Borgulya et al. (Helvetica Chimica Acta (1989) 72, 952-968), for example there are described analogous compounds which have an unsubstituted phenyl ring.
This known synthetic route, and similar synthetic routes for related benzophenones, has considerable disadvantages, which are primarily associated with the high number of steps of the synthesis and the time/apparatus expenditure associated therewith. Moreover, relatively expensive starting materials, such as vanillin and 4-bromotoluene, are required for this synthetic route.
Surprisingly, it has now been found that these disadvantages can be largely avoided by subjecting a compound of formula (III) and a reactive acid derivative of formula (IV) to a Friedel-Crafts acylation, cleaving off one of the two substituents R.sup.1 and separating the resulting salts of compounds of formula (I) from the isomeric salts of compounds of formula (II) according to one of the processes described below.